Title previous year. He complained of reduced grip

Title
of Article: A Mimic of Immune Mediated Neuropathy

Corresponding Author: Dr Simon
Cronin, Department of Neurology, Cork University Hospital, Cork, Ireland. [email protected]

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Co-author: Dr Eimear McAuliffe, Department
of Neurology, Cork University Hospital, Cork, Ireland.

Co-author: Dr Mary Clare McKenna, Department
of Neurology, Cork University Hospital, Cork, Ireland

 

Word Count: 1,296

 

Abstract:

A
54-year-old male presented with a 2 year history of progressive distal weakness
with numbness. He has a background of type 2 diabetes mellitus, hypertension
and a history of alcohol excess. His initial examination demonstrated weakness
and sensory loss distally. His symptoms progressed rapidly over six months.
Following investigation, he was commenced on a trial of intravenous
immunoglobulin (IVIg) which resulted in clinical improvement. A diagnosis of
distal axonal chronic inflammatory demyelinating polyneuropathy was made. It is
important to evaluate clinical symptoms and signs, to recognise patterns of
peripheral neuropathy and thus arrive at a diagnosis.

 

 

 

 

 

 

A
difficult case

A
Mimic of Immune Mediated Neuropathy

Eimear
McAuliffe1, Mary Clare McKenna1, Simon Cronin1

1.Department
of Neurology, Cork University Hospital

 

Case Report

A
54-year-old right handed male presented with a 2-year history of progressive
painful tingling in his hands and feet. 
The hands were more affected than the feet, and symptoms were more
prominent on the left. He was unable to do buttons or tie shoelaces over the
previous year. He complained of reduced grip strength. His motor symptoms were
ongoing 1 year. He felt as if he was “standing on nails”. He complained of
swollen feet in the mornings. He was diagnosed with type 2 diabetes mellitus 1
year ago and was treated with oral hypoglycaemic agents. He had a background of
hypertension, elevated body mass index and a history of alcohol excess. His
sister had died of motor neuron disease at age 62 with disease onset age 58.
There was no history of recent infection.

On
examination, he had a broad-based gait. Cranial nerves were intact. Neck
flexion and extension were 5/5. Bilaterally, shoulder abduction was 4++/5,
wrist extension 4+/5 bilaterally, opponens pollicis and abductor digiti minimi
3+/5 bilaterally. Pin prick and temperature were reduced distally to mid
forearm. Joint position sense and vibration were preserved in the upper limbs.
Deep tendon jerks were normal in the upper limb. There was pseudoathetosis and
impaired coordination in the upper limb with eyes closed.  There was dysmetria in the upper and lower
extremities. Hip and knee power was 5/5. There was bilateral mild ankle dorsiflexion
weakness 4+/5. Pin prick and temperature were reduced distally to knees. Joint
position sense was preserved in the lower limb. Vibration was reduced to the
tibial tuberosity bilaterally. There were no fasciculations. Deep tendon jerks
were absent. Plantars were downgoing. Allodynia was noted. He was soft Rhomberg
positive.

Peripheral
neuropathy blood screening tests demonstrated an elevated glycated haemoglobin
(HbA1c) 63 mmol/mol (20-42 mmol/mol). Fasting lipids including total
cholesterol (6.6 mmol/L, (3.5 – 5 mmol/L) and triglycerides (3.9 mmol/L, (0.3 –
1.7 mmol/L) were elevated. Additional blood tests included normal urea and
electrolytes, thyroid function tests, haematinics, erythrocyte sedimentation
rate and serum protein electrophoresis. HIV, Hepatitis B and Hepatitis C,
syphilis and Lyme serology were all negative. Rheumatoid factor, antinuclear
and anti-neutrophil cytoplasmic were negative.

The
initial clinical diagnosis was moderately severe diabetic axonal motor and
sensory neuropathy. Despite improving glycaemic control by reducing HbA1c to
58mmol/mol (20-42mmol/mol), his symptoms progressed over the next 6 months. He
had increasingly painful tingling in his hands and feet. Numbness now extended
to his mid thighs. Sensory symptoms were again more pronounced on the left. His
hands and feet felt weaker. His pain was worse. Clinically, he now had wasting
of the intrinsic muscles of the hands. Opponens pollicis and abductor digiti
minimi 3/5 bilaterally. Fasciculations remained absent. Pin prick and
temperature were reduced distally to upper arms. Joint position sense and
vibration remained preserved in the upper limbs. He was distally weak with
ankle and hallux dorsiflexion 3+/5. Vibration remained reduced to the tibial
tuberosity bilaterally.  Joint position
sense was now impaired in the feet. He was Rhomberg positive.

Nerve
conduction studies and electromyography (NCS/EMG) showed absent sensory
responses throughout and reduced motor amplitudes with reduced conduction
velocity.

Given
the rapid progression of his symptoms, the initial diagnosis of diabetic axonal
neuropathy was re-evaluated. The differential based on clinical and NCS/EMG
findings included severe diabetic neuropathy, chronic inflammatory
demyelinating polyneuropathy (CIDP) or a late presentation of an inherited
neuropathy. He was referred for sural nerve biopsy which excluded vasculitis
and amyloidosis; it could not differentiate between diabetic neuropathy, CIDP
or an inherited neuropathy (such as a connexin 32 mutation). Magnetic resonance
imaging (MRI) of the cervical spine showed no focal signal abnormality or
syrinx in the cervical cord, bilateral foraminal stenosis at C3-C4, and right
foraminal stenosis at C5-C6 with possible impingement of the exiting nerve
roots. There was no gadolinium enhancement of the nerve roots. Cerebrospinal
fluid analysis demonstrated protein 622mg/L which was high (200-400 mg/L).
Anti-myelin associated glycoprotein (anti-MAG) and antiganglioside 1 (GM1)
antibodies were negative. Connexin 32 genetic screening excluded point
mutations, making a diagnosis of axonal Charcot Marie Tooth unlikely. A 5-day
trial of intravenous immunoglobulin (IVIg) was given (2g/kg split over 3 days).
On the 4th day hand dexterity improved significantly; the patient was now able
to fasten buttons. Bilateral shoulder abduction was 5/5, wrist extension was
5/5, opponens pollicis and abductor digiti minimi 3+/5.

The
maximum effect was sustained for 10 days and he then returned to an improved
baseline. A diagnosis of reversible, immune mediated neuropathy responsive to
IVIg was made. Possible diagnoses included an atypical upper limb predominant
CIDP phenotype or multi-focal motor neuropathy with conduction block
superimposed upon diabetic neuropathy. The patient was further treated with
2g/kg of IVIg over 3 consecutive days given monthly for 3 months, then every 6
weeks. He remains clinically stable at an improved baseline and is independent
in his activities of daily living. He mobilises independent of a frame or
stick. He attends for infusions of IVIg every 6 weeks.

 

Discussion

The
aetiology of peripheral neuropathy may be difficult to ascertain. It may be
inherited or acquired. Diagnosis is based on history, clinical examination,
laboratory investigations, and neurophysiology. Electrodiagnostic tests help to
differentiate conditions that affect the nerve axon (axonopathies) or the
myelin sheath (myelinopathies)1. In a review of 205 patients with
undiagnosed peripheral neuropathy referred to the Mayo Clinic, a diagnosis was
made in 76% of patients1. A hereditary cause was found in 42%,
inflammatory neuropathy such as CIDP in 21%, and the remaining 13% were due to
other diseases such as diabetes, malignancy and vitamin deficiencies.

Chronic
Inflammatory Demyelinating Polyneuropathy is an inherited condition which is
characterised by slow onset of sensorimotor symptoms which are generally
symmetrical. There is not just one phenotype and it has been suggested that
CIDP is part of a spectrum of similar conditions. Due to the variation in
clinical presentation identification of the disease can be difficult. In this
case, a diagnosis of CIDP is supported by a history of gradual onset of
proximal and distal weakness in the upper and lower extremities, with a raised
CSF protein, electrodiagnostic findings, and clinical response to IVIG. The
asymmetry is a little atypical suggesting additional inflammatory nerve root
involvement however there was no enhancement of nerve roots on gadolinium MRI.
Anti ganglioside 1 antibodies were negative however this can often be the case.
There is now evidence that CIDP can be due to antibodies directed at Schwann
cells or nodal antigens and not just against myelin2. It is now
thought that nodal antibodies can be present in 30% of patients with CIDP2. 

The
main differential diagnosis was an acquired diabetic sensorimotor
polyneuropathy causing demyelination due to poor glycaemic control however this
would be expected to present with symmetric distal sensory loss, with or
without distal weakness. Autonomic dysfunction may also feature. Symptoms
worsened despite improving glycaemic control. Simultaneous presence of diabetes
mellitus type 2 (DM2) and CIDP has been seen in clinical practice however it is
unknown if they are genetically linked. Some studies have suggested an
increased risk of CIDP in patients with DM2. There is also the dilemma of how
to treat CIDP in patients with diabetes mellitus as systemic steroids are known
precipitants of insulin resistance therefore treating with immunoglobulin is
often more sensible.  

Helpful
clues in making the diagnosis include defining the anatomy, clarifying the
distribution of weakness, the extent of sensory involvement, the presence or
absence of upper motor neuron involvement, the temporal evolution and family
history if known. This case highlights the importance of the clinical pattern
and temporal evolution of peripheral neuropathy in making a diagnosis. It shows
how diagnosis is often not clear at presentation and clinicians should
systematically examine the history, clinical exam, laboratory investigations,
and neurophysiology before choosing the most suitable treatment regimen for the
patient in question.

 

Key
Points

1.         The importance of the clinical pattern
in making a diagnosis of peripheral neuropathy

2.         The importance of correlation of
clinical evaluation and electrodiagnostic findings

3.         Symptom response to treatment can help
with diagnosis.

4.         The emerging role of autoimmune
antibodies in the diagnosis of peripheral neuropathy

 

References

1.         Barohn, R. and Amato, A. (2013).
Pattern-Recognition Approach to Neuropathy and Neuronopathy. Neurologic
Clinics, 31(2), pp.343-361.

2.         Mathey EK, Park SB, Hughes RAC, et al.
Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to
phenotype. Journal of Neurology, Neurosurgery, and Psychiatry.
2015;86(9):973-985. doi:10.1136/jnnp-2014-309697.

 

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